There are currently 15.7 million people or 5.9% of the population in the United States who suffer from diabetes mellitus. Each day approximately 2,200 people are diagnosed with diabetes and roughly 798,000 people will be diagnosed this year. Diabetes is the seventh leading cause of death (sixth-leading cause of death by disease) in the United States.
Diabetes mellitus, more commonly known as diabetes, is a disease in which body does not produce and/or properly use insulin, a hormone that aids the body in converting sugars and other foods into energy. In a non-diabetic individual, insulin is produced in the pancreas at the islets of Langerhans in response to an increase in glucose in the gut and/or blood. Insulin then acts in conjunction with the liver to control glucose metabolism in the body. While diabetes is typically considered as a blood-sugar disease, diabetes may result in numerous life-threatening complications. For example, diabetes may lead to various microvascular diseases, such as coronary artery heart disease, retinopathy, nephropathy, and neuropathy. Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (high blood sugar levels) resulting from the defective secretion or action of insulin. Nowadays, the complication of diabetes can be controlled by maintaining the glucose level in advance to prevent or defer the development of illness. Therefore, it is worth to develop a powerful anti-diabetic drug for controlling the patient's glucose level within a normal range.
There are several types of diabetes mellitus, which is classified based on their aetiology:
1. Type 1: Insulin dependent diabetes mellitus (IDDM), commonly referred to as Type 1 diabetes, is an auto-immune disease. Type 1 diabetes occurs when body's immune system attacks and destroys beta cells in the islets of Langerhans in the pancreas. Beta cells normally produce insulin. If the beta cells are destroyed, no insulin can be produced, and glucose stays in the blood, where high level of glucose can cause serious damage to all organ systems in the body. Type 1 diabetes may affect as many as 1 million people in the United States.
2. Type 2: Non-insulin dependent diabetes mellitus (NIDDM), commonly referred to as Type 2 diabetes, is a metabolic disorder resulting from body's inability to produce sufficient insulin or properly use the insulin produced. Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. Roughly 90 percent of all diabetic individuals in the United States suffer from Type 2 diabetes, which is usually associated with obesity and a sedentary lifestyle.
3. Specific type: The aetiology of this type of diabetes, which is a secondary diabetes, can be traced to other diseases such as Hemochromatosis and Cushing's syndrome.
4. Gestational Diabetes
Under normal conditions, patients suffering from type 1 diabetes must take or inject insulin for body's necessary functions. This means undergoing multiple injections daily, or having insulin delivered through an insulin pump, and testing their blood sugar by pricking their fingers for blood about six or more times a day. Patients suffering from Type 2 diabetes often control their glucose level in the blood by taking anti-diabetic drug orally. The present oral anti-diabetic drugs are classified into five types.
1. Sulfonylurea-based derivative: This type of medicine binds to a sulfonylurea receptor existing in an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells, resulting in the inhibition of the KATP channel and depolarization of membrane potential. As a result, voltage-gated Ca2+ channels are opened, and the rise in intracellular calcium leads to increased secretion of (pro)insulin.
2. Biguanide-based derivative: Metformin is the most common drug in this class. Metformin stimulates a hepatic enzyme, AMP-activated protein kinase (AMPK), which enhances GLUT4 translocation to increase glucose uptake and utilization. In addition, Metformin increases the sensitivity of muscle cells to insulin, increasing muscle cell's ability to store glucose.
3. Thiazolidinedione-based derivatives: this class of drugs binds to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma). This kind of drugs could enhance the insulin activity in the muscles and fatty tissues, as well as reduce the glucose synthesis in the liver and promote the conversion of blood sugar into the fatty acids.
4. α-glucosidase inhibitor: This kind of drug is capable of inhibiting the activities of both pancreasα-amylase and intestinal α-glucosidase, so that the degradation of starch and carbohydrate is inhibited. Therefore, the glucose absorption into the intestine is reduced.
5. Meglitinide-based derivatives: This kind of drugs binds to 36 kDa receptor existing in an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells, leading to the inhibition of the ATP-dependent potassium channels in beta cells and opening of the calcium channels. The resulting calcium influx causes the cells to secrete insulin. These drugs act quickly when taken orally. Thus, it is recommended that these drugs be taken before meals to help control the rise in blood sugar levels after meals.
In addition, earlier studies showed that several catechol-containing natural products, such as caffeic acid (Hsu F L, Chen Y C, Cheng J T et al., Planta Med, 66(3), 228-230, 2000), extracts of propolis from north China (Fuliang H U, Hepburn H R et al., Pharmacol Res, 51(2), 147-152, 2005), extracts of propolis from Brazil (Matsui T, Ebuchi S, Fujise T et al, Biol Pharm Bull, 27(11), 1797-1803, 2004), capsaicin (Tolan I, Ragoobirsingh D, Morrison E Y, Phytother Res, 18(1), 95-96, 2004), curcumin (Mahesh T, Sri Balasubashini M M, Therapie 2004, 59(6): 639-644), and the like, are effective in lowering blood sugar.
Diabetes is often associated with cardiovascular diseases, particularly, ischaemic heart disease, which is a disease characterized by reducing blood supply to the heart. Ischaemic hear disease often results in acute myocardial infarction (AMI), a congestive heart failure, arrhythmia, and sudden death. It is the most common cause of morbidity and mortality in most industrial countries. According to statistics published by the United State government in 2001, death resulting from ischaemic heart disease accounts for 20% of total death numbers (approximately 60 million deaths per year) (Myerburg R J., Cardiovasc Electrophysiol., 12, 369-381, 2001), wherein the majority of the deaths is caused by sudden death of people falling ill for first time. In addition, it is estimated that there are approximately 110 million Americans suffering from AMI in 2001, including new cases and recurrence cases. Many patients noted above develop subsequent complications, which cause heart failures and deaths. In recent years, the increase in aging population and other common complications, such as the obesity and the diabetes, puts a greater burden on public health budgets for ischaemic heart disease. Therefore, how to effectively minimize ischaemia and reduce injuries associated with reperfusion of ischaemic hearts has become an important medical issue.
Two key factors impact the outcome of treating ischaemic heart diseases. One is to take actions to prevent or minimize cardiac arrhythmia. Most patients suffering from acute myocardial infarction die from arrhythmia; some of these patients may survive because of spontaneous recovery of the heart rhythm or after a cardiopulmonary resuscitation (CPR). However, the success in the treatment for cardiac arrest has been dismal in the past thirty years.
Another factor is to minimize the size of myocardial infarction due to ischaemia or ischaemia-reperfusion. The degree of recovery depends on the extent of injury of the cardiac muscle after ischaemia or ischaemia-reperfusion. The standard protocols for treating acute myocardial infarction include giving patients thrombolytic agent or performing percutaneous transluminal coronary angioplasty (PTCA). These treatments could immediately recover the blood flow to the heart. Although such treatments are helpful in preventing further deterioration of the ischaemic cardiac muscles, they may lead to complications. Particularly, in high risk populations, surgery may lead to prolonged contractile dysfunction (or stunning), perioperative myocardial infarction, and cardiac failure. Therefore, there still exists a need for novel auxiliary treatments to be used in conjunction with the perfusion therapy to prevent injuries to the cardiac muscle caused by ischaemia or ischaemia-reperfusion.
The present invention provides a series of catechol-based derivatives, which promotes blood flow in the coronary artery, suggesting that they are capable of preventing or treating injuries of the cardiac muscles caused by ischaemia or ischaemia-reperfusion. Embodiments of the present invention not only solves the problems described above, but also is easy to implement.